17-substitutedcyclohex[2, 3] androsta-23 (3), 4-dien-22-ones and derivatives



17-SUBSI'ITU'IEDCYCLOHEX[2,31 ANDROSTA- 23(3), 4-DlEN-22-ONES ANDDERIVATIVES Norman W. Atwater, Des Plaines lll., assignor to G. D.

Searle 8; Co., Chicago, 111., a corporation of Delaware r t r t NoDrawing. Filed Dec. 11, 1958, Ser.No. 719,556

\ H2 R i i V i t wherein R is selected from the group consistingethydroxy, lower-alkanoyloxy," acetyl, and (a-ethylenedioxy)- ethylradicalsf LoWer-alkanoyloxy radicals which R may represent are the acylradicals of carboxylic acids such as formoxy, acetoxy, propionyloxy,butyryloxy, valeryloxy,

chained isomers of the foregoing.

. .:The compounds of this invention are novel in that they contain anadditional six-membered ring which has been attached to ring A of thecyclopentanophenanthrene structure characteristic of the steroidmolecule. This results in a pentacyclic structure, the parenthydrocarbon of which would be named cyclohex[2,3]androstane. Thusthepresent invention relates to l7-substituted-cyclohex- .[2 ,3 androsta23(3),4 dien 22 ones, l7-substituted V caproyloxy, heptylyloxy,caprylyloxy, and branched- 2,9393% Patented June 7,

isolated to afford the sodium salt of 2-hydroxymethylehe progesteroneZO-ethylene ketal. The latter is treated with ,B-diethylaminobutanonemethiodide in the presence of sodium methoxide and the product isolatedto afford 2-(3- oxobutylyprogesterone ZO-ethylene ketal. By treating thelatter compound with an aqueous solution ofpotassium hydroxideinmethanol and isolating the product, 17-

(a ethylenedioxy) ethylcyc1ohex[2,3]androsta 23(3),1- dien-22-one isobtained. Treating 17 (a-ethylenedioxy)ethylcyclohex[2,3landrosta-23(3),4-dien-22-one with dilute hydrochloric acid andisolating the product yields 17-acety1cyclohex[2,3]-androsta-23(3),4-dien 22one, a compound of the present invention.@ v

Treating 17 hydroxycyclohex[2,3landrosta 23(3),4- dien 22-one witha'lower alkanoic anhydride in the presence of pyridine and isolating theproduct affords the 17- (lower alkanoyloxy)cyclohex E2,3]androsta23(3),4- dien-22 ones of the preeentinvent-ion.

3 The 23 (3 -dehy'dro-compounds of the present invention are prepared bytreating the corresponding 23(3),4- dehydrdcorhpounds with one molecularequivalent of hydrogen in the presence of a hydrogenation catalyst andisolating the productlHAs a specific example, 17-acetyl- 25cyclohex[2,3]ai1drosta 23 (3),4 dicn 22 one is treated with onemolecular equivalentof hydrogen in the presence of 5%palladium-on-carbon catalyst and the product isolated to affordl7-acetylcyclohex[2,3]androst-23- (3)-en-22-one. 3 Theperhydro-compounds of the present invention are prepared by treating thecorresponding 23(3),4-dehydrocompounds with two molecular equivalents ofhydrogen in the presence of a hydrogenation catalyst and isolating theproduct. For example,17-acetoxycyclohex[2,3]androsta-23(3),4-dien-22-one is treated with twomolecular equivalents of hydrogen in the presence of 5%palladiumon-carbon catalyst and the product isolated to yieldll7-acetoxycyclohex[2,3]androstan-22-one. The compounds of the presentinvention have valuable pharmacological properties. They possess, forexample,

activity characteristic of cortisone; that is, they are able cyclohex[2,3]androst 23 3 cut- 22 ones, and 17- .substituted-cyclohex [2,3androstan-ZZ-ones.

Suitable starting materials for the synthesis .of the compounds of thisinvention are,- tor example, testosterone and progesterone20-ethyleneketal.

The synthesis involves three steps, the first of which consists oftreating one of the aforementioned. starting materials with ethylformate in the presence of a condensing agent and. isolating the productto yield the 2-hydroxymethylene derivative as the sodium salt. Thelatter is-tr eated with fi-diethylaminobutanone methiodide in thepresence of a suitable condensingagent and isolation of l the productalfords. the 2-(3-oxobutyl)compound. -'Ihe iinal step, which iscyclization of the 2-(3-oxobutyl) deriuative, consists of treating thelatter with an aqueous .solution ofpotassium hydroxide in methanol andisolating .the produ ct to afford, the cyclohex[2,3]androsta-23(3-),4-

dien 22-ones of the. present invention substitutedlin the ,l'l positionwith a hydroxy or (at-ethylenedioxy)ethyl radical. As a specific exampleof this three-step process, gprogesterone ZO-ethylene ketal listreatediwith ethyl forl mate in the presence of sodium hydride. and theproduct tothe other as kilograms to liters.

to inhibit the hyperemia associated with iritis, an inflammation of theeye. Theyhave progestational activity also.

temperatures are given indegrees centigrade (0 C.),

Quantities of materials are expressed in parts by weight and in-parts'byvolume which bear the same relation one EXAMPLE 1 .1 Z-hydroxycyclohex[2,3 androsia-Zj (3 ,4-dien-22- ne To a solution of 15 parts by weightof testosterone in benzene solution washed once with water. The combinedaqueous layers are acidified tdpH-S wit h-6 N H'Cl and Q the resultantprecipitate extracted into ether. Theether solution is dried overanhydrous sodium sulfate, then evaporated to dryness. The residual oilon standing yields -crystals-Which are. recrystallized from other toafford The invention will appear more fully from the examples a" r Thelayers are separated and the pure 2-hydroxymethylenetestosterone, M.P.about 168.5- 171".

To a solution of sodium methoxide prepared from 0.55: part by weight ofsodium and 60 parts by volumeof methanol is added first-7 .35 parts byweight ofthe above: prepared i hydroxymethylenetestosterone then" asolution pf'fl-diethylaminobutanone methiodide, prepared from 6.62 partsby weight of .B-diethylaminobutanone and 1725 parts by weight ofmethyl'iodide in 40 .parts by volume of anhydrous methanoL. Theresulting mixtureis stirred under nitrogen :at room temperature for 20hours then acidified with glacial acetic acid and diluted with 1000parts by volume of water. Theresultant precipitate is extracted intoether, the ether solution washed with water, dried over anhydrous sodiumsulfate .andevaporated to dryness. This crude residue-may be .carriedonto the next step satisfactorily or may be crystallized fromacetone-water and acetone-petroleum ether. to afford pure2-.(3-oxobutyl) testosterone, M.P. about 1765:1772

To .a solution of crude 2e(3-oxobutyl)testosterone in 700 parts byvolume of -methanol is added .a' solution of 26 parts by weight ofpotassium hydroxide in 6 -pants' by volume of water- The reactionmixture allowed to stand at room temperature for.2 hours vthenevaporatedton small volume-in vacuo. Dilution with 500 parts by volume ofwaterprecipitates a solid which is extracted; into ether. The ether-solutionis washed with water, dried over anhydrous sodium sulfate andevaporated to drynessin vacuo. Irituration Withacetone produces thecrude sol-id product which on recrystallization from. acetone yieldspure 17 -hydroxycyclohex[2,3lam drosta-23(3),4dien-22-one, M.P. about212-214 EXAMPLE 2 1 17-acet0xycycl0hex [2,3 androsta-Zd (3,4-dien-22-0ne herein described processes l7-is'ovaleryloxycyclohex[2,3]androsta-23 (3 ,4-dien-22 one 'is' obtained.

. EXAMPLE 3 17 --(a ethylenedioxy)ethylcyclohex[2,3,]andr0sta 23- I V i(3 ),4-die n-22-0ne To a solution of.26.5 parts by weight ofprogesterone 20-.ethylene-ketal and 22 parts by volume of'ethyl formate.in420parts by volume of dry benzene is added 6.5 parts by weight ofsodium hydrida' The -.mixture .is allowed to stand under nitrogen atroom temperature for 45' hours with occasional swirling. The mixture istreated with parts by volume of methanol and the solid removed byfiltration and-"washed first with benzene then-with-ether.

' essence by volume of methanol. The reaction mixture is stirred undernitrogen at room temperature for l6hours. The solid product is collectedby filtration and recrystallized from methanol and isopropyl ether toafford pure 2-(3- oxobutyl)progesterone 20-ethylene ketal, M.P. about Aslurry of 0.5 part of '2-(3-oxobutyl)progesterone ZG-ethylene ketalwithasolution of 1.75 parts by weight of potassium-hydroxidein 5 partsby volume ofxwater and 45 parts by volume of methanol is heated atreflux under nitrogen for 5 hours.v The cooled mixture is filtered andthe solid recrystallized from acetone and .isopropyl ether to yield purel7-(a-ethylenedioxy)ethylcyclohex[2,3 landrosta-23 (3 ,4-dien-22-one,M.P.

EXAMPLE 4 Z-acetyIcycIQhex [2,3 androsta-23.(3 .4=dien-2 2-0ne 7 partsby volume of water. The resulting solutionis 1 I allowed to stand atroom temperature for 16 hours, then diluted with200 parts by volume ofwater. The resulting precipitate is collected by filtration andrecrystallized from isopropyl ether to aiford pure v17-acetylcyclohex-[2,3]androsta.-23 (3),4-dien-22-one, M.P. about 110.5- 1 l 1.5

EXAMPLE 5 1 7-hydroxycyclohex [2,3 landrosl-23 (3 -en-22-0 ne A solutionof 1 part by weight of 17-hydroxycyclohex- V [2,3]androsta-23.(3),4-dien22-one in 50 parts by volume of ethyl acetate is hydrogenated at oneatmosphere in the presence of 0.1 part by weight of 5% palladium-on 7carbon catalyst until one molecular equivalent of hydrocyclohex [2,3landrost-Z} (3 -,en-22-on'e, M.P. about .191 51- .l-93 1 EXAMPLE '6 1 V1meemx clohextaamama-23 3 ten-zz-one Toa solution of 2 paits-byweight'of 17-hydroxycyclo- "hex-[2,3landroste23(3)-en-22-one "in 15parts by volume of pyridine is added 7.5; parts by volumeof aceticanhydride and the mixture allowedto stand at-roomtemperature for 20hours. Dilution with 200 'parts 'by vro'ltime of water precipitates asolid which is collected' by' filtration and recrystallized from ethanoland-isopropyl ether to 'afiordIpure 17-acetoXycyclohexE2;3landirosb23-(3)-en-22one,' M.P.about 213.521-5.

By substituting an equivalent quantity ofbutyric an- I I hydride andotherwise proceeding-accordingto the herein .Thecrnde salt is purifiedby washing with 25.0 partsby V yolumezof water and ,dryingby azeotropicdistillation of the'water from a slurry of themoist salt with 100 partsby volume of ethanol and 1500 parts by volume of benzene. I When there.is approximately 300 parts by volume of the slurry remaining, the saltis collectedfby filtration and dried in air.

' To a solution of Bediethylaminobutanone methiodide,

' prepared from 4.1 'parts by weightof .fi-diethlamino- Jbutanone and4.06 .parts by weight of methyl iodide, in

.SU parts :by volume of anhydrous rnethanol'is added 0.12

by weight ofzsodium methoxide and a slurryotthe salt ajs obtained intheprevious paragraph with 100 parts described processes,'IFbutyroxycycloheX [2,3 andros't-23- (3) -en -22-one is obtained. 3

' EXAMPLE 7 'em-22-one about To a-solution of2 parts by weight t 17(methylenef h. In

5 EXAMPLES.

l7-acetyl cyclhex[2,3]andr0st-23(3)-en-22-0ne A solution of 1 part byweight of l7-acetylcyclohex- [2,3]androsta-23(3),4-dien-22-one in 100parts by volume of ethyl acetate together with 0.15 part by weight of.palladium-on-carbon catalyst is shaken in a hydrogen atmosphere at oneatmosphere pressure. The reaction is stopped when one molecularequivalent of hydrogen has been absorbed and the catalyst removed by.

filtration. Evaporation of the filtrate to dryness in vacuo andrecrystallization of the residue from isopropyl ether affords pure17-acetylcyc 1ohex [2,3 androst-23 (3 -en-22- one, M.P. ISO-181.

EXAMPLE 9 A solution of 1 part by weight of l7-hydroxycyclohex-[2,3landrosta-23(3),4-dien-22-one in 50 parts by volume of ethyl acetateis added to 0.1 .part .by weight of 5% pal-.

1 7-acetoxycycl0hex [2,3] androstan-ZZ-one A solution of 1.04 parts byweight of l7-acetoxycyclohex[2,3]androsta-23 (3),4-dien-22-one in .partsby volume of ethanol is hydrogenated at one atmosphere in the presenceof 0.1 part by weight of 5% palladium-oncanbon. catalyst until twomolecular equivalents of hydro gen are absorbed. Removal of the catalystby filtration and evaporation of the filtrate to dryness in vacuo leavesa residue from which pure 17-acetoxycyclohex[2,3landrostan-22-one, M.P.about 142.5-143.5, is obtained by recrystallization irom ethanol. Itsinfrared absorption spectrum shows maxima at 5.80 and 7.95 microns.

By substitutingyan equivalent quantity of 17-isovalery1- oxycyclohex[2,3androsta-23 (3 ,4-dien-22-one and otherwise proceeding according totheherein described processes,l7-isovaleryloxycyclohex[2,3landrostan-22-one is obtained.

EXAMPLE 11 17 (a ethylenedioxy)ethylcyclohex[2,3landr0stan 22- one To asolution of 2 parts by weight of 17-(a-ethy1enedioxy) ethylcyclohex [2,3androsta-23 3 ,4-dien-22-one in 80 parts by volume of ethyl acetate isadded 0.2 part by weight of 5% palladium'on-carbon catalyst and themixture hydrogenated at one atmosphere until two molecular equivalentsof hydrogen are absorbed. The catalyst is removed by filtration and thefiltrate evaporated to dryness in vacuo producing a residue which isrecrystallized from isopropyl ether to afford pure17-(a-ethylenedioxy)ethylcycloheX[2,3landrostan-ZZ-one. Its infraredabsorption spectrum possesses maxima at 5.84, 9.37 and 9.50 microns.

' EXAMPLE 12 1 7-acety1cyclohex [2,3] a-n drostan-ZZ-one A mixture of 1part by weight of 17-acetylcyclohex- [2,3]androsta-23(3),4-dien-22-onedissolved in 100 parts by weight of ethyl acetate with 0.15 part byweight of 5% palladium-on-carbon catalyst is hydrogenated at oneatmosphere until two molecular equivalents of hydrogen are absorbed. Thecatalyst is removed by filtration and the filtrate evaporated to drynessin vacuo leaving a residue which is recrystallized from isopropyl etherto yield pure 17-acetylcyclohex[2,3landrostan-ZZ-one. It possessesmaxima in the infrared at 2.90, 5.83 and 9.40 microns.

What is claimed is: 1 1. A compound of the structural formula wherein Ris selected from the group consisting of by droxy, lowen'alkantsyloxy,acetyl, and (aethylenedioxy)- ethyl radicals.

2. A compound of the structural formula mo R HsC

wherein R is selected from the group consisting of hydroxy,lower-alkanoyloxy, acetyl, and (a-ethylenedioxyy ethyl radicals.

3. A compound of the structural formula like wherein R is selectedlfromthe group consisting of hydroxy, lower-alkanoyloxy, acetyl, and(a-ethylenedioxy) ethyl radicals. I

4. A compound of the structural formula OCCHI 6. A compound of thestructural formula CHI HIC

7., A compound of the tructuralfozmuiz o-om - 10. A compound ofiithastructural formula 11. componndlof the shfu ctural formula CH: o-oH, v

12. A compound of .:;the .fst1;uctu'Ia1 formula H36 1 H10 1 I $13;A..waompound of thestructuraLformula V i (I? as H8O m-0H3 -15 Aooompoundofzthe structural formuia GHQ list) 5 V No refemn ce's cited.

1. A COMPOUND OF THE STRUCTURAL FORMULA
 2. A COMPOUND OF THE STRUCTURALFORMULA
 3. A COMPOUND OF THE STRUCTURAL FORMULA